1. Field of the Invention
The invention relates to treatments for vasomotor symptoms in surgically or chemically castrated prostatic cancer patients and pharmaceutical dosage forms for use in treating the patients.
2. Background
Prostate cancer is the second most common cancer and the second leading cause of cancer death in American men, with approximately 1 in 6 men diagnosed. As with most cancers, no cure exists for prostate cancer, however, several treatments are available to reduce its progression, including androgen deprivation therapy (“ADT”), prostatectomy, and orchiectomy. The most commonly used treatment is ADT.
Androgens play a key role in the progression of prostate cancer, especially testosterone and dihydrotestosterone. Androgen deprivation can be achieved surgically, by orchiectomy (removal of testicles), or medically by use of drugs. However, ADT has side effects that may decrease a subject's quality of life. One side effect is hot flashes, which can start without warning, last up to 30 minutes, and may vary in frequency from several times a week to more than a dozen episodes per day. Hot flashes are associated with increased pulse rate, anxiousness, irritability, and nausea, and may be experienced as a suddenly occurring feeling of heat that spreads quickly from the face, to the chest and back, then over the rest of the body, and can be accompanied by profuse sweating.
Generally, they are a source of great physical and mental distress to the prostate cancer patient.
The best therapeutic effect on hot flashes is achieved by replacement therapy with sex steroids. However, androgens are contraindicated in male prostate cancer subjects.
The symptoms of hot flashes have been rarely reported in prostate cancer patients treated with estrogens such as diethylstilbestrol (“DES”), or with cyproterone acetate (“CPA”) or megestrol acetate (“MA”) either alone or in combination with DES. There is no apparent difference in vasomotor hot flash response with respect to whether the primary therapy is surgical or chemical castration, or among patients receiving various formulations of different luteinizing hormone-releasing hormone (“LHRH”) agonists. Treatment with pure antiandrogens (such as flutamide) in addition to surgical castration or to LHRH agonist treatment does not appear to significantly influence either the frequency or severity of hot flashes nor the response to treatment. Estrogens such as DES may be effective to decrease hot flashes, but at the risk of gynecomastia and increased cardiovascular morbidity.
MA, a progestational hormone, has been shown to reduce hot flashes in men and women. Various studies of MA, including for treatment of prostate cancer and reduction of hot flashes, have been reported in the literature. See, e.g., Loprinzi et al., N. Engl. J. Med. 331: 347-352 (1994); Wehbe, et al., Mayo Clin. Proc., 72: 932-934, 932 (1997); Dawson et al., J. Urol. 153:1946-1947 (1995); Mann et al., Arch. Intern. Med. 157: 1651-1656 (1997).
CPA, a synthetic 21-carbon hydroxyprogesterone derivative, is disclosed in U.S. Pat. No. 3,234,093, which is incorporated herein by reference. CPA is a steroidal antiandrogenic agent that inhibits the action of adrenal and testicular androgens on prostatic cells, resulting in total androgen blockade. Additionally, due to the antigonadotropic effects of its progestogenic activity, CPA causes a centrally mediated reduction in testicular secretion of androgens. CPA is approved for use in many regions of the world, including Europe, Asia, and South America, as well as in Australia and Canada. It is used as a component of oral contraceptives and in the treatment of acne, seborrhea, hirsutism, precocious puberty, hypersexuality and in the treatment of prostate cancer. The pharmaceutical preparations ANDROCUR® (cyproterone acetate, Berlex Canada CYPROSTAT® (cyproterone acetate, Bayer plc), DIANE® (cyproterone acetate/ethinyl estradiol, Schering Ltd), and DIANETTE® (cyproterone acetate/ethinyl estradiol, Schering Ltd), are CPA-based products. Manufacturers of these products include Schering AG, Berlin, Germany and Berlex, Canada.
Side effects most frequently recorded with CPA treatment relate to the hormonal effects of the drug. These include impotence, inhibition of spermatogenesis and gynecomastia. These reactions are usually reversible upon discontinuation of therapy or reduction in dose. The drug is also associated with rapid falls in serum testosterone levels, which may also produce such central nervous system effects as fatigue, weakness, and headache.
CPA has been investigated for use in treating hot flash symptoms associated with surgical or medical castration. In a double-blind, crossover trial, Eaton and McGuire treated 12 prostate cancer subjects with troublesome post-orchiectomy hot flashes with CPA or placebo. Eaton A C and McGuire N., Lancet 8363:1336-1337 (1983). The frequency of hot flashes was significantly reduced during the 3 weeks that CPA (300 mg daily) was given. Ronzoni et al. treated 37 subjects with bothersome hot flashes with CPA or MA. Ronzoni et al., Arch Ital Urol Androl 70(1): 37-40 (1998). A therapeutic efficacy of 80% and 70% reduction in hot flashes was observed following administration of CPA and MA, respectively.
Similarly, in a much larger clinical trial in 273 subjects, who had previously undergone orchiectomy, the number of subjects experiencing hot flashes and outbreaks of sweating decreased after treatment with CPA (150 mg daily) compared with placebo. Krämer et al., Proceedings of the 3rd International Symposium on Recent Advances in Urological Cancer Diagnosis and Treatment, Paris (1992) June 17-19: pp 3-7. Hot flashes were experienced by 33% of subjects receiving CPA and 61% of subjects receiving placebo, while only 24% of CPA-treated subjects had outbreaks of sweating compared with 47% of placebo-treated subjects. Furthermore, in those subjects receiving CPA who continued to experience hot flashes or sweating, the frequency and severity were decreased. Id. and Barradell et al., Drugs & Aging 5/1: 59-80 (1994). In several randomized well-controlled clinical trials in prostate cancer subjects, CPA given in combination with LHRH agonists was associated with a reduction in the percentage of subjects reporting hot flashes. deVoogt et al., J Steroid Biochem Molec Biol 37: 965-969 (1990); DiSilverio et al., Eur Urol 18 (suppl 3):54-61 (1990); Thorpe et al., Eur Urol, 29(1): 47-54 (1996).
The Androcur® Monograph, Berlex Inc., Canada (1997), indicates a general improvement in the subjective assessment of the quality of life in 70% of 367 evaluable patients participating in worldwide studies on CPA. The criteria listed are weight gain and pain relief. The patients considered included ones who received CPA as monotherapy, an estrogen refractory group, and orchiectomized patients. It appears that dosage forms included oral and i.m. injection and that the doses varied. Most patients who received oral CPA were dosed at 200 to 300 mg/day. The lowest oral dose given to orchiectomized patients was indicated to be 100 mg/day.
Dose-related hepatic toxicity in humans has been reported with the prolonged use of CPA. Toxicological studies have revealed, however, that administration of CPA to humans does not pose a serious risk of hepatotoxicity. A retrospective liver toxicity analysis was performed on 89 patients with advanced prostatic cancer who received continuous additional antiandrogenic treatment with 50 mg/day CPA. Hinkel et al., Eur. Urol. 30:464-470 (1996).
Moreover, a thorough review on the toxicology of CPA was published by Rabe et al., Drug Safety, 14(1):25-38 (1996). In a multi-center surveillance study of long-term CPA use in over 2500 patients, the treatment group included men and women. The men were treated at dosages of either more than 200 mg/day or from 100 to 200 mg/day CPA. No correlation was found between the duration of CPA treatment and the prevalence of liver enzyme elevations.
U.S. Pat. No. 6,165,504 (“the '504 patent”) relates to methods for treating hot flashes in a castrated prostatic cancer patient by orally administering from 25 mg to 150 mg CPA per day, preferably from 50 mg to 100 mg CPA per day.